Compounds based on the ergoline ring system: ##STR1## have a suprising variety of physiological actions. For example, many of the amides of lysergic acid, which is D-8.beta.-carboxy-6-methyl-9-ergolene, have valuable and unique pharmacologic properties. The trivial name "ergoline" is given to the above structure and the 9, 10 double bonded compounds related to lysergic acid are called 9-ergolenes rather than 9,10-didehydroergolines. The name D-ergoline or D-8-ergolene or D-9-ergolene is used herein in naming specific compounds. The letter "D" indicates that the C-5 carbon atom configuration has the asbolute stereochemistry designated as R and that the hydrogen is .beta.--above the plane of the ring system. However, modern usage has tended to omit the "D" on the ground that the newly synthesized ergolines or ergolenes are universally derivatives of natural products such as lysergic acid or elymoclavine, all of which have R stereochemical--"D" series--configuration and in which the stereochemical integrity at C-5 is maintained. It should be understood that all of the compounds or classes of ergolines or ergolenes disclosed herein also have the R stereochemical configuration, whether or not the specific or generic name is preceded by a "D".
Among the pharmacologically active amides of lysergic acid are included the naturally occurring oxytoxic alkaloids (ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc.), synthetic oxytocics such as methergine and the synthetic hallucinogen--lysergic acid diethylamide or LSD. The amides of D-6-methyl-8-carboxyergoline, known generically as the dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Recently, it has been found by Clemens, Semonsky, Meites, and their various co-workers that many ergot-related drugs have activity as prolactin inhibitors and are also useful in treating Parkinsonism. References embodying some of the newer findings in the field of ergoline chemistry which form part of the background of this invention, but are not necessarily relevant prior art, include the following: Nagasawa and Meites, Proc. Soc. Exp't'l. Biol. Med., 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech. Chem. Commun., 33, 577 (1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id, 441; Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 2200 (1971) 42, 1209 (1977); Schaar and Clemens, Endocr., 90, 285-8 ( 1972); Clemens and Schaar, Proc. Soc. Exp. Biol. Med., 139, 659-662 (1972), Bach and Kornfeld, Tetrahedron Letters, 3225 (1974), Conodi et al, J. Pharm. Pharmac., 25, 409 (1973), Johnson et al, Experentia, 29, 763 (1973); Stone, Brain Research, 72, 1977 (1974) Lieberman et al, J.A.M.A., 238, 2380 (1977), Cassady et al J. Med. Chem., 17, 300 (1974), Sweeney et al, Con. Res. 35, 106 (1975); Fehr et al, Helv. Chem. Acta, 53, 2197 (1970), Bernardi et al, Il Farmaco-Ed. Sci., 30, 789 (1975) and Cassady and Floss, Lloydia, 40, 90 (1977). Recently issued patents in the field of ergolines or of lysergic acid derivatives include the following: U.S. Pat. No. 3,923,812, U.S. Pat. No. 3,920,664, U.S. Pat. No. 3,901,894, U.S. Pat. No. 3,929,796, U.S. Pat. No. 3,944,582, U.S. Pat. No. 3,934,772, U.S. Pat. No. 3,954,988, U.S. Pat. No. 3,957,785, U.S. Pat. No. 3,959,288, U.S. Pat. No. 3,966,739, U.S. Pat. No. 3,968,111, U.S. Pat. No. 4,001,242, U.S. Pat. No. 4,122,177, U.S. Pat. No. 4,075,213, U.S. Pat. No. 4,075,212, U.S. Pat. No. 3,985,252, U.S. Pat. No. 3,904,757, U.S. Pat. No. 4,096,265, U.S. Pat. No. 3,752,888, U.S. Pat. No. 3,752,814, U.S. Pat. No. 4,110,339, U.S. Pat. No. 4,054,660. Many other related and older patents can be found in U.S. Patent Office Classification Files 260-256.4 and 260-285.5.
2-Azaergolines and 2-aza-8(or 9)-ergolenes have not heretofore been reported.